The overall theme of this Program Project Grant is the identification of abnormalities of myocardial energy metabolism that occur with heart failure, and the effects of these abnormalities on left ventricular function and remodeling. The severely decompensated heart switches to a fetal metabolic phenotype, characterized by downregulation of free fatty acid (FFA) oxidation and enhancement of glucose oxidation. Two important questions remain unanswered: 1) it is not known whether this metabolic alteration is an adaptive or maladaptive mechanism, nor if it plays a role in the progression from compensated to decompensated heart failure (HF); and 2) the molecular mechanisms responsible for the altered metabolic phenotype of the failing heart are poorly understood. Our preliminary data indicate that chronic partial inhibition of FFA oxidation delays the onset of decompensation in a canine model of dilated cardiomyopathy. We have also shown a reduction in the protein expression of retinoid X receptor-alpha (RXRalpha), a key regulator of the FFA oxidative pathway, in end-stage pacing-induced HF. The overall goal of this Project is to test the hypothesis that changes in expression and activation of RXRalpha and of its obligate co-receptor peroxisome proliferator receptor-alpha (PPARalpha) are key determinants of the altered myocardial metabolic phenotype in HF and play an important role in the progression toward cardiac decompensation. Studies will be performed in dogs with pacing-induced HF. The first specific aim is to determine the time course of alterations in myocardial metabolic phenotype and in protein expression and activation of RXRalpha and PPARalpha at sequential time points during the progression of HF and after post-pacing recovery. Changes in hemodynamics, cardiac function and substrate metabolism measured in vivo will be correlated with the activity of key enzymes of the substrate oxidative pathways and with the expression and activation state of RXRalpha, PPARalpha measured in snap-frozen cardiac biopsies. The second specific aim is to determine whether early myocardial switch to preferential oxidation of carbohydrate delays the progression of HF. During development of HF, myocardial FFA oxidation will be partially suppressed at pre-mitochondrial or intra-mitochondrial level. The third specific aim is to determine whether a sustained activation of RXRalpha or PPARalpha can prevent the alterations in myocardial metabolic phenotype and accelerate the progression of HF. RXRalpha and PPARalpha will be alternatively activated by specific ligands administered during the development of HF.